The process by which herpes simplex virus type 1 (HSV-1) reactivates from latency to cause recurrent herpetic disease is poorly defined. Although considerable circumstantial evidence suggests that ICPO (an HSV-1 transactivator) plays a central role in reactivation, direct evidence to support this hypothesis is lacking. A limiting factor in the study of ICPO mutants in vivo (as with many other HSV-1 mutants) has been that ICPO mutants do not replicate as efficiently as wild-type HSV-1 in animals. Consequently, it is unclear from previous analyses if the decreased reactivation of ICPO- mutant viruses from trigeminal ganglion is due to inefficient neuronal colonization and latent infection, or a requirement for ICPO in HSV-1 reactivation. The goals of the studies proposed herein is to a) develop methods that allow the equal establishment of latency with mutant and wild-type HSV-1 in mice, and using these methods b) obtain definitive evidence to either support or reject the hypothesis that ICPO plays a role in HSV-1 reactivation.